McCune-Albright Syndrome

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McCune-Albright syndrome

Definition

A disorder characterized by abnormalities in bone development, skin pigmentation, and endocrine gland function.

Description

The McCune-Albright syndrome is an uncommon disorder in which a mutation distributed across various cell populations results in a wide variety of clinical features. The most notable features are abnormal bone development, pigmented skin spots, and endocrine gland dysfunction.

Genetic profile

Scientists have identified a specific genetic defect that causes McCune-Albright syndrome. The defect is a mutation in the GNAS1gene , which is associated with a type of G protein. These proteins are present in a wide variety of cells in the body. G proteins are part of the system of proteins and enzymes that regulate communication between cells and various agents such as hormones and the nervous system. If a cell's G protein is abnormal, this sets off a chain reaction that causes the cell to multiply inappropriately and the subsequent cells produce too much hormone. The mutation first occurs in a single cell during the early stages of formation of the embryo. This cell multiplies into many other cells that eventually become part of the bones, skin, and endocrine glands. The severity of the syndrome is dependent on the percentage of cells involved. The earlier the mutation

occurs, the more cells are affected. There is some evidence that a second mutation must occur before the clinical manifestations become evident.

The McCune-Albright syndrome is not hereditary.

Demographics

This syndrome is uncommon. As of 1996, there were only 158 cases reported in scientific papers. Of course, this figure probably underestimates the true prevalence of the syndrome, since only patients with typical or severe clinical features were likely to be reported. The female to male ratio is approximately two to one.

Signs and symptoms

The McCune-Albright syndrome is classically characterized by the three main features described below.

Abnormal bone development

Pockets of abnormal fibrous tissue develop within the bone, which may cause deformity, fractures, and nerve entrapment. Most of these lesions appear during the first decade of life. The pelvis and femur, or thigh bone, are the most commonly involved areas of the skeleton. Bony abnormalities in the skull can cause blindness or deafness. The majority of patients with McCune-Albright syndrome have many of these lesions, hence the name polyostotic fibrous dysplasia.

In addition to these fibrous lesions, some patients develop osteosarcoma, which is a malignant tumor of the bone. Although it has not been proven, these tumors may originate from the fibrous lesions within the bone.

Pigmented skin spots

Patients with McCune-Albright syndrome typically have pigmented skin lesions called café au lait spots. These are flat areas of discoloration of the skin that may be associated with a variety of conditions. Those that are found in McCune-Albright syndrome have irregular borders. They are located on one side of the body, usually on the buttocks or lower back. Sometimes these lesions are present at birth.

Endocrine gland dysfunction

The McCune-Albright syndrome is striking for its association with a number of endocrine abnormalities. Endocrine glands are those that secrete hormones directly into the blood stream to be transported to other tissues of the body. In McCune-Albright syndrome, one or more of these glands secrete abnormally high amounts of hormone.

The most common endocrine abnormality in McCune-Albright syndrome is excessive function of the gonads, which are ovaries in females and testicles in males. The ovaries secrete estrogen and the testicles secrete testosterone. When these organs secrete too much estrogen or testosterone in children, the result is early puberty. Females are more commonly affected than males. In fact, early puberty in a girl is the hallmark sign of McCune-Albright syndrome. Typically, these girls will develop secondary sexual characteristics, such as breasts and pubic hair, before the age of nine. Menses also begins early. Sometimes the normal sequence of development is disrupted, in that affected girls might have menses before breast or pubic hair development.

Hyperfunction of the pituitary gland also occurs in McCune-Albright syndrome, resulting in excess production of growth hormone and/or prolactin. Excess growth hormone leads to acromegaly , or marked overgrowth of certain bones and tissues, especially in the face and extremities. Some people with acromegaly grow to very tall stature. Acromegaly in McCune-Albright syndrome affects boys and girls equally. If too much prolactin is produced, then breast tissue will secrete milk inappropriately, both in boys and girls. This is called galactorrhea. In some patients, the pituitary gland dysfunction is caused by a tumor.

Other endocrine glands that may be hyperactive are the thyroid and adrenal glands. The thyroid gland produces thyroid hormones, which help regulate the body's metabolism. If excess thyroid hormones are produced, that is, hyperthyroidism, then patients may have diarrhea, weight loss, nervousness, tremor, and rapid heartbeat. In some patients, the hyperthyroidism is caused by thyroid nodules. The adrenal gland produces several hormones in the steroid hormone class, such as cortisol, aldosterone, and testosterone. Cortisol is most commonly over-produced. Similar to the pituitary gland, hyperfunction of the adrenal gland in McCune-Albright syndrome is sometimes caused by tumors.

Another feature of McCune-Albright syndrome is phosphate deficiency caused by excess excretion of phosphate in the urine. Since phosphate is a vital mineral for bone formation, this results in soft bones and some degree of pain. This condition is called rickets in children and osteomalacia in adults. There are two theories that have been proposed to explain the loss of phosphate in the urine. First of all, it is thought that the fibrous bone lesions may produce an agent that circulates through the blood stream to the kidneys that makes the kidneys unable to retain phosphate. Secondly, perhaps the kidneys are intrinsically unable to retain the appropriate amount of phosphate.

It is important to emphasize the variability of clinical features among patients with McCune-Albright syndrome. Not every patient has the three features of bony lesions, pigmented skin spots, and endocrine abnormalities. Each patient is affected differently. There are also rare subtypes of the syndrome in which patients have hepatitis, cardiac arrythmias, or intestinal polyps.

Diagnosis

There is no single test that is diagnostic for McCune-Albright syndrome. Certain clinical features can be easily observed, such as skin pigmentation and early puberty. The bony abnormalities can be confirmed by x ray. Blood tests for hormone levels can detect endocrine gland dysfunction.

Treatment and management

Likewise, there is no specific treatment that cures the disease. Testalactone, a drug that inhibits estrogen production, has been successful in the short term treatment of girls with early puberty, but long term treatment has not been very effective. Patients with pituitary tumors may benefit from drugs to reduce tumor size, or surgery to remove the tumors. Thyroid nodules can be treated by surgical removal or destruction with radioactive iodine. In addition, adrenal tumors can be removed by surgery.

Prognosis

The life span in patients with McCune-Albright syndrome is essentially normal. Women who experienced early puberty as girls are generally fertile.

Resources

BOOKS

"Multiple-Organ Syndromes: Polyglandular Disorders." In Cecil Textbook of Medicine, edited by Lee Goldman, et al. 21st ed. Philadelphia: W.B. Saunders Company, 2000.